21-desoxy-16,17-cyclic acetals



United States Patent 0 3,226,383 21-DESOXY-16,17-CYCLIC ACETALS Howard J. Ringold and Carl Djerassi, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Apr. 28, 1960, Ser. No. 25,236

Claims priority, application Mexico, May 18, 1959,

54,598, 54,599 19 Claims. (Cl. 260-239.55)

The present invention relates to novel cyclopentanophenanthrene derivatives.

More particularly the present invention relates to cyclic 160a, 170c-k6ialS and 160:, 17a-acetals of 6a-halo (fiuoro or chloro)-9ahalo(fiuoro or chloro)-A -pregene- 16oz, 17a-diol-3,20-diones having an oxygen function such as keto or ,B-hydroxy at C-ll. Moreover, there may be present in the molecule double bonds at C-1,2 and/or C6,7.

The novel compounds of the present invention have anti-androgenic activity, anti-estrogenic activity and exhibit a marked anti-inflammatory activity particularly upon topical administration.

The novel compounds of the present invention are illustrated by the following formulas:

3,226,383 Patented Dec. 28, 1965 In the above formulas, Z indicates a double bond or a saturated linkage between C-1 and 0-2; X and X represent chlorine or fluorine; Y represents keto or }8- hydroxyl and R and R represent hydrogen or the residue of a hydrocarbon radical containing up to 8 carbon atoms of straight, branched, cyclic or mixed aliphatic-cyclic chain, saturated or unsaturated, including aromatic groups.

The new compounds IV of the present invention wherein X is fluorine may be prepared by a process illustrated by the following equations:

Hz-0 S -CHa mixture with ethyl acetate and acetic acid or in mixture with xylene or tertiary butyl alcohol. By a combination of these methods or by refluxing the A -compound with chloranil in n-amyl alcohol, there was obtained the A -trienes.

In the above reaction X, X, Y, Z, R and R have the same meaning as previously set forth.

For transforming the 17fi-ketol side chain of the starting compounds into the 17;.3-acetyl group, that is, for producing the desired final products, there was first formed the 21-mesylate (II) by reaction with methanesulfonyl chloride in pyridine, the mesylate group was then substituted by iodine by reaction with sodium iodide in mixture with acetone, and finally the resulting 21- iodo compound (III) was transformed into the 17 8- acetyl-compound (IV) by refluxing with sodium bisulfite in mixture with aqueous methanol, or by reaction with chromous chloride in acetone.

However, where the starting compound contained the 6-chloro-A -3-keto grouping, it was first necessary to protect the chlorine atom at C-6 prior to transformation of the 17-ketol side chain into the 17B-acetyl group. This was accomplished by reacting the 160:, 17u-cyclic ketal or 16a, l7a-cyclic acetal derivative of 6(a or 19)- chloro-9ix-halo-16u-hydroxy-cortisone 21-acetate or of 6(a or B)chl0IO-9a-ha10-1Goo-hYdl'OXY-hYdl'OCOI'tiSOIlC 21- acetate with ethyl orthoformate at room temperature for 1 hour in a solvent such as dioxane and in the presence of p-toluenesulfonic acid to form the 3-ethyl enol ether derivative. The C-21 acetoxy group was then hydrolyzed as by treatment with 1% methanolic potassium hydroxide at 0 C. and the resulting 21-hydroxy compound was then transformed into the 21-mesylate, the 21-iodo and finally the 21-desoxy compound as hereinabove set forth. Upon subsequent treatment with a mineral acid, such as dilute hydrochloric acid in acetic acid, at room temperature, the enol ether group was hydrolyzed to regenerate the A -3-keto group, thus affording the corresponding 16a, 17a-cyclic acetal or ketal of 6a-ch1oro- 9a-halo(fluoro or chloro)-A -pregnene compound. A double bond may then be introduced at C-1,2 by refluxing with selenium dioxide, preferably in tertiary butanol, in the presence of pyridine and under an atmosphere of nitrogen for 48 hours or a double bond may be introduced at C-6,7 by refluxing with chloranil preferably in CHZO Acetyl (EH20 Acetyl Y o o f; I v R i i o: EtO

oH,-o s-CH; 011,011 (1:0 0 0:0

/R /R Y/\ 0 Y o X 'o X 'o Et0 m0 In practicing the process according to the above reactions, there were used as starting materials the 16a,17acyclic ketals or l6oc,17a-CyCliC acetals of 6-halo(fiuoro or droxy)-A -pregnene-16a,17a-diol-3,20-diones and their 1- dehydro derivatives, disclosed in copending application Serial No. 819,545 filed on June 11, 1959, now Patent No.

3,126,375, and the 6-dehydro derivatives thereof as here inafter more fully described.

The starting compounds utilized for the preparation of the novel compounds of the present invention, disclosed in the aforementioned copending application, were obtained by treatment of a 6ot-halo (fluoro or chloro)-9a-halo (fiuoro or chloro)-16a-hydroxy derivative of cortisone, hydrocortisone, prednisone or prednisolone or the 21 esters thereof, disclosed in copending application Serial No. 762,232, filed September 22, 1958 and Serial No.

753,626, filed August 7, 1958, now Patent No. 2,997,489,

with an aldehyde or ketone such as formaldehyde, paraldehyde, acetaldehyde, benzaldehyde, acetophenone, methyl ethyl ketone, diethyl ketone, furfural, chloracetone and the like under anhydrous conditions and in the presence of a catalyst such as copper sulphate, dry hydrogen chloride or perchloric acid without using a solvent or in the presence of a solvent such as dioxane. The C-21- ester group was hydrolyzed by reaction with sodium methoxide in methanol solution at low temperature under an atmosphere of nitrogen and under anhydrous conditions to thus aiford the l6u,17a-cyclic acetals or 1 605170:- cyclic ketals of the 6a-halo-9whalo-16u-hydroxy derivatives of cortisone, hydroc-ortisone, prednisone and prednisolone.

For the preparation of the starting 6-dehydro compounds, a 21-ester of the latter compounds was heated with chloranil in xylene. However, upon heating with chloranil in n-amyl alcohol, the cortisone and hydrocortisone derivatives were transformed into the corresponding 1,6-bisdehydro compounds; the latter compounds were also formed from the corresponding 6-dehydro derivatives by refluxing with selenium dioxide in tertiary butanol and in the presence of catalytic amounts of pyridine.

The reactions may be modified within wide limits both with respect to the reagents and solvents employed as with respect to the conditions of temperature and time. Thus for example, instead of 21-mesylate, there was prepared the 2l-tosylate; a 2l-alkyl(aryl)-sulfonate may be converted in only one step into the desired 21-d'es0xy compound by refluxing with sodium iodide in mixture with acetic acid.

The following examples serve to illustrate but are not intended to limit the scope of the invention:

EXAMPLE I A solution of 3 g. of 16a,17u-acetonide of 60:,9oz-difluoro-16a-hydroxy cortisone, described in copending application Serial No. 819,545, in 60 cc. of a mixture of pyridine and chloroform (9:1) was cooled to 0 C. Under stirring, there was added batchwise 1.0 g. of methanesulfonyl chloride; the mixture was kept for 14 hours at 0 C., diluted with 60 cc. of chloroform, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Thus there was obtained the crude 21- mesylate of 1:6,17OL-3C6t0fild6 of 6a,9u-difiuoro-16a-hydroxy cortisone.

A solution of the crude compound in cc. of acetone was treated with 2 g. of sodium iodide and refluxed for 2 hours. Most of the acetone was removed by distillation, the residue was diluted with water and the precipitate formed was collected by filtration, Washed with water and dried under vacuum. There was thus obtained the crude 16a,17 x-acetonide of 6a,9 x-difluoro-2l-iodo-A -pregnene- 16a,17oL-diO1-3,1 1,20-trione.

To a solution of this iodo compound in 120 cc. of methanol and 12 cc. of water was added 3 g. of sodium bisulfite and and mixture was refluxed for 2 hours. Most of the methanol was removed by distillation under reduced pressure, the residue was diluted with water and the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane. There was thus obtained the L,17t1-21Ct01'1ld of 6a,9a-difluoro-A -preg nene-16a,17a-diol-3 ,11,20-trione.

EXAMPLE II By the method of Example I, but employing p-toluenesulfonyl chloride instead of methanesulfonyl chloride, there was prepared the 2l-tosylate of 16u,l7ot-acetonide of 606,90L-difl11OIO-160t-hYdPOXY-COIIISOI1C.

A solution of 2.0 g. of the above compound in 100 cc. of glacial acetic acid was treated with 6.5 g. of sodium iodide and the mixture was refluxed for 2 hours, poured into ice water and extracted several times with methylene chloride; the extract-s were combined, washed successively with aqueous sodium carbonate solution, sodium sulfite solution and water and then evaporated. By crystallization of the residue from acetone-hexane, there was obtained the 16o,17oc-3.Cot0l1id6 of 6a,9a-difluoro-A -pregnene-16ot,17a-diol-3,11,20-trione, identical with the one prepared in accordance with Example I.

EXAMPLE III A mixture of 5 g. of l6a,l7oc-H.C6t0nid6 of 60:,9oz-difluoro-l6a-hydroxy-cortisone 21-acetate, 8 g. of chloranil and 200 cc. of xylene was refluxed for 12 hours, cooled and diluted with ether. The solution was washed with water, 5% sodium carbonate solution and again with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. By chromatography of the residue on neutral alumina, there was obtained the 16u,17a-acetonide of 6,9u-difill0IO-16ochydroxy-6-dehydro-cortisone 21-acetate.

A suspension of 1 g. of the l6a,17a-acetonide of 611,91 difiuoro-16whydroxy-6-dehydro-cortisone l l-acetate in 10 cc. of absolute methanol was treated with 10 cc. of sodium methoxide in absolute methanol (prepared by dissolving 60 mg. of sodium metal in 10 cc. of absolute methanol), with stirring under an atmosphere of nitrogen at 0 C. for 1 hour. After precipitating with saturated aqueous sodium chloride solution containing a few drops of acetic acid, the product was extracted with methylene chloride, washed with water, dried over anhydrous sodium from acetone-hexane, thus affording the free 16a,l7aacetonide of 6,9a-difluoro-16a-hydroxy-6-dehydro-cortisone.

In accordance with the methods described in Examples I and II, the 16a,170c-21C6IOI1ld6 of 6,9zx-ditluoro-l6a-hy droxy-6-dehydro-cortisone were converted into the 160i, Uni-acetonide of 6,9a-difluoro-A -pregnadiene-16a,l7adio1-3,1 l,20-trione.

A mixture of 2 g. of the 16a,17a-Z1C6tOnlde of 60,9ocdifluoro-l6a-hydroxy-6-dehydro-cortisone, 100 cc. of tertiary butanol, 300 mg. of selenium dioxide and 0.2 cc. of pyridine was refluxed under an atmosphere of nitrogen for 48 hours, filtered through celite and the filtrate was evaporated to dryness under reduced pressure. The residue was refluxed for 1 hour with decolorizing charcoal in acetone, filtered from th charcoal and the filtrate was evaporated to dryness. Chromatography of the residue on washed alumina yielded the 16a,17u-acetonide of 6,9ocdifluoro-16a-hydroxy-1,6-bisdehydro-cortisone which was then converted into the l6a,l7a-acetonide of 6,9a-difluoro-A -pregnatriene-16a,l7a-diol-3,l1,2O-trione by the method described in Example I.

EXAMPLE IV In accordance with the methods described in Examples I and II, the 16a,17u-methyl-phenyl ketal of 6a,9a-difluoro-16a-hydroxy-hydrocortisone, described in copending application, Serial No. 819,545, was converted into the l6a,17-a-methyl-phenyl ketal of 6oc,9a-difiuoro-A -pregnene-l1p,16a,17a-triol-3,20-dione.

In accordance with the methods described in Examples I and II, the 1600,1700-3C6t01'1ld65 of the compounds listed under A and described in the aforementioned copending application were converted into the l6a,17o-acetonides of the compounds listed under B.

EXAMPLE XII In accordance with the method described in Example III, the starting compounds of Example V through XI were converted into the corresponding 6-dehydro compounds and then by the methods described in Examples I and II were finally converted into the corresponding 21- desoxy-l6a,Nix-acetonide derivatives, i.e., the l6a,17otacetonides of 8 EXAMPLE xnr A mixture of 5 g. of the 21-acetate of the 16u,17oacetonide of 6a-chloro-9a-fluoro-l6a-hydroxy-cortisone, 5 cc. of ethyl orthoformate, 50 cc. of dioxane and 500 mg. of p-toluenesulfonic acid monohydrate was stirred at room temperature for 1 hour, 5.0 cc. of pyridine was then added followed by the portionwise addition of ice water, under stirring and until complete precipitation of the reaction product. The mixture was kept in the refrigerator for 2 hours and the precipitate was collected by filtration, washed with water, dried and recrystallized from acetonehexane; there was thus obtained the l6a,l7a-acetonide of 6 chloro 9a fluoro 3 ethoxy 21 acetoxy A pregnadien-16a,17 -diol-l1,20-dione, namely the 3-ethylenol-ether of the 21-acetate of the 16a,l7a-acetoni-de of 6-chloro-9oa-fluoro-16a-hydroxy-cortisone.

In order to obtain the enol ether compound with the free 2l-hydroxyl group, the steroid was treated with 1% methanolic potassium hydroxide solution for 1 hour at 0 and under an atmosphere of nitrogen, using 50 cc. of the methanolic potassium hydroxide solution for l g. of the steroid. The mixture was then neutralized with acetic acid, concentrated under reduced pressure, diluted with Water and the precipitate was collected by filtration and purified by recrystallization from acetone-hexane.

A solution of 5 g. of the 16a,17a-acetonide of 6- chloro 9a fluoro 3 ethoxy-A -pregnadiene-16a,l7a, 21-triol-11,20-dione in 50 cc. of pyridine was treated with 3 cc. of methanesulfonyl chloride at 0 C. and kept overnight at this temperature, then poured into ice water and the precipitate was collected, washed with water and dried. There was thus obtained the 2l-mesylate of the l6oc,17oc acetonide of 6 chloro-9a-fluoro-3ethoxy-A3 pregnadiene-l6a,l7a,21-triol-11,20-dione, which was used for the next step without further purification.

A solution of the above compound in 200 cc. of acetone was mixed with 3 g. of sodium iodide and refluxed for 2 hours. Most of the acetone was then removed by distillation, the residue was diluted with water and the precipitate was collected, washed with water and dried. There was thus obtained the l6a,l7a-acetonide of 6 chloro 9oa-- fluoro 21 iodo 3 ethoxy A pregnadien-l6a,17u-diol-11,20-dione in crude form, which was dissolved in 200 cc. of methanol and 20 cc. of water; 5 cc. of sodium bisulfite was added and the mixture was refluxed for 2 hours. Most of the methanol was removed by distillation under reduced pressure, the residue was diluted with water and the precipitate was collected, washed with water andthen treated with 2 cc. of concen trated hydrochloric acid in 200 cc. of glacial acetic acid, kept at room temperature for 2 hours and diluted with ice water. There was thus obtained the 16a,l7a-acetonide of 6a-chloro-9a-fluoro-A -pregnene-16a,l7ix-diol-3, 11,20-trione which was purified by recrystallization from acetone-hexane.

A mixture of 1 g. of the above compound, 2 g. of chloranil, 25 cc. of ethyl acetate and 5 cc. of glacial acetic acid was refluxed under an atmosphere of nitrogen for 72 hours; the cooled mixture was washed with aqueous 10% sodium hydroxide solution until the washings were colorless, dried over anhydrous sodium sulfate and the ethyl acetate evaporated. Chromatography of the residue on neutral alumina yielded the 16a,l7a-acetonide of 6- chloro-9a-fluoro-A pregnadiene 16ot,170cdi0l3,11,20- trione.

A mixture of 500 mg. of the above compound, 300 mg. of selenium dioxide, 20 cc. of t-butanol and a few drops of pyridine was refluxed for 18 hours under an atmosphere of nitrogen and then filtered through celite and diluted with water; the precipitate was collected, washed with water, dried and purified by chromatography on neutral alumina. There was thus obtained the :,1700- acetonide of 6-chloro 9a-fluoro-A -pregnatriene-16a, 17a-dio1-3,11,20-trione.

1 g. of the IMAM-acetonide of Got-ChlOIO-Qcz-fiHOIO- A pregnane-16or,l7a-diol-3,11,2G-trione was subjected to the method of dehydrogenation with selenium dioxide described above, to produce the IMAM-acetonide of 6a- ChlOI'O-QOL-fiHOI'O A -pregnadiene-16a,l7a-diol-3,11,20- trione which was then subjected to the reaction with chloranil described above to furnish finally the 16,l7aacetonide of 6-chloro 9a-fluoro-A -pregnatriene-16a, 17a-diol-3,1l,20-trione, identical with the one produced by dehydrogenation of the A -compound at C6,7 and then at C1,2.

EXAMPLE XIV In accordance with the method described in the preceding example, there were prepared the 21-acetate of the 3-ethyl enol ether of the 16a,17a-acetonides of 6,9adichloro-16u-hydroxy cortisone, 6-chloro9wiuoro-16zxhydroxy-hydrocortisone and 6,9zx-diCh1OIO-16ot-hYdfOXY- hydrocortisone which were converted into the free 21- alcohols and subsequently into the corresponding 16,17aacetonides of 6ix,9a-dichloro-A -pregnene-16a,17a-diol-3, 11,20-trione, of 6a-chloro-9a-fiuoro-M-pregnene-116,1604, l7a-triol-3,20-dione, of 6a,9a-dichloro-M-pregnenel15, 16a,17a-triol-3,20-dione.

By treatment with selenium dioxide, as set forth in the preceding example, the latter compounds were transformed into the l6a,l7a-acetonides of 6a,9a-dichloro- A pregnadiene 16a,170c diol 3,11,20-trione, of 6achloro 90c fiuoro n -pregnadiene-l1fi,16a,17a-triol- 3,20-dione and of 6a,9ot-dichioro-A -pregnadiene-l15, 16a,17a-triol-3,20-dione. By further treatment with chloranil as set forth in the preceding example, there were formed the 1604,17ot-21C6t011id68 of 6,9a-dichloro-A pregnatriene-160;,17a-di0l-3,11,20-trione, of 6-chloro-9afluoro-A -pregnatriene-115,16,17u-triol-3,20-dine and of 6,90; dichloro A regnatriene-I 1,B,16ot,17ot-tIiOl- 3,20-dione.

By treatment with chloranil and a mixture of ethyl acetate and acetic acid as described in Example XIII, the 16a,17 x acetonide of 611,9 dichloro-a -pregnene-l6e, 17a-diOl-3,l1,20-t1i011, the 16,17wacet0nide of 6achloro 9a fluoro A -pregnene-11B,16a,17a-triol-3,20- dione and the 16a,17a-acetonide of 6a,9a-dichloro-A pregnene 11fi,16u,17ot triol-3,20-dione were converted into the 160,l7a-E1C81O1lid6 of 6,90:-dichloro-A -pregnadiene-16a,17e-triol-3,l1,20-trione, the 16a,17a-acetonide of 6-chlore-9wfiuoro-A -pregnadiene-11fi,16 x,17a-triol- 3,20-dione and the 16a,l7a-acetonide of 6,9a-dichloro- A pregnadiene 116,16a,17a-triol-3,20-dione, respectively.

EXAMPLE XV By substituting the 16u,17a-benzaldehyde acetal derivative of the starting materials in all of the preceding examples for the 1604,1704-21CE1011id8 derivative, there was obtained the corresponding cyclic l6u,l7a-benzaldehyde acetal derivative of the products formed in all of the previous examples.

There may also be used other cyclic ketal and acetal derivatives of the starting compounds such as the 1611,1712- formaldehyde acetal, the 16a,17a-methyl-ethyl-ketal, the 16a,17oc-acetaldehyde acetal, the 16a,17u-methyl-phenyl ketal to afiord the corresponding 2l-desoxy derivatives set forth in the preceding examples.

16 We claim: 1. A compound of the following formula:

wherein Z is selected from the group consisting of a double bond between C-1 and C-2 and a saturated linkage between C1 and C-2; X and X are each selected from the group consisting of fluorine and chlorine; Y is selected from the group consisting of keto and fi-hydroxy; and R and R are each selected from the group consisting of hydrogen and a hydrocarbon radical containing up to 8 carbon atoms.

2. The 16a,17a-formaldehyde acetal of 6-fluoro-9achloro-A -pregnadiene-16a,17a-diol-3,11,20-trione.

3. The 16u,17u-acetonide of 6,9a-difluoro-A -pregnadiene-l1fi,16a,17a-triol-3,20-di0ne.

5. The 16a,17a-acetonide of 6,9u-dichloro-A -pregnadiene-16a,17adiol-3,11,20-trione.

6. The 16u,17a-benza1dehyde acetal of 6,9OL-dlflll01'0- A -pregnatriene-16a,17u-diol-3,11,20trione.

8. The 16a,17u, acetonide of 6 chloro 904 fluoro- A -pregnatriene-16a,17a-diol-3,11,20-trione.

El. 1601,17 lower alkylidenedioxy-6,9a-dichloro-A pregnadiene-l1fi-ol-3,20-dione.

10. l6oc,17oc lower alkylidenedioxy 6 ,9a difiuoro- A -pregnadiene-l1fi-ol-3,20-dione.

11. 16a,17a lower alkylidenedioxy 6 ,9 diiluoro- A -pregnadien-3,11,2O-trione.

12. 16a,17a lower alkylidenedioxy 6 chloro rfluoro-A -pregnadiend 1,20-trione.

13. 16a,17a lower alkylidenedioxy 6 fiuoro 90cchloro-A -pregnadiene1 1 fi-ol-3,20-dione.

14. 1604,1704 lower alkylidenedioxy 6,9 difluoro- A -pregnatriene-1 15-01-3 ,20-dione.

15. 16a,17a lower alkylidenedioxy 6 fluoro 9achloro-A -pregnatriene-1 1 B-o13,20-dione.

16. :,170: lower alkylidenedioxy 6,901 dichloro- A -pregnatriene-l 1 3-01-3 ,20-dione.

17. 16a,17a lower alkylidenedioxy 6 chloro -9afluoro-A -pregnatriene-1 1 ,8-ol-3,20-dione.

18. The 16ot,17ot acetonide of 6,90 difluoro A pregnatriene-l1,8,16m,17a-triol-3,20-dione.

19. The 16u,17u acetonide of 6 fiuoro 9m chloro- A -pregnatriene-11p,16u,17vt-triol-3,20-dione.

No references cited.

LEWIS GOTTS, Primary Examiner.

MORRIS LIEBMAN, LESLIE H. GASTON, IRVING MARCUS, Examiners. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 